Methods for remodeling neuronal and cardiovascular pathways

ABSTRACT

The present invention provides a method of administration of an agent which acts to remodel neuronal or vascular pathways for the long term management of sexual dysfunction in both males and females. In a preferred embodiment, the invention provides a method of ameliorating or reversing pathogenic vascular degradative modeling in the ilio-hypogastric-pudendal arterial bed and genitalia comprising administering to a human patient in need of such treatment a therapeutically effective amount of an anti-pressor agent. The anti-pressor agent comprises one or more compounds selected from the therapeutic classes of direct vasodilators such as hydralazine and NO donors, ACE inhibitors, angiotensin-II receptor antagonists, α 1 -adrenergic receptor antagonists, β-adrenergic receptor antagonists, calcium channel blockers, and phosphodiesterase inhibitors. The anti-pressor agent may be co-administered with a diuretic compound, and is administered either chronically at low dose, or for short periods of time at doses higher than are typically used for the treatment of hypertension. In certain embodiments of the method of the invention, the anti-pressor agent is co-administered with a diuretic agent and/or prostaglandin-E 1 .

CROSS-REFERENCE TO RELATED APPLICATIONS

This patent application is a divisional application of U.S. patentapplication Ser. No. 09/382,749, filed Aug. 25, 1999 and issued Sep. 4,2001 as U.S. Pat. No. 6,284,763, which claims priority from U.S.Provisional Patent Application Ser. No. 60/098,178, filed Aug. 26, 1998.

TECHNICAL FIELD

The present invention relates to medical methods of treatment,pharmaceutical compositions, and use of anti-pressor agents tomanufacture such pharmaceutical compositions. More particularly, thepresent invention concerns the administration of an agent which acts toremodel neuronal or vascular pathways for the long term management ofsexual dysfunction in both males and females.

BACKGROUND OF THE INVENTION

The physiology of an erection or sexual arousal in both the male andfemale involves central nervous system initiation, neural pathwayactivation, and vascular smooth muscle relaxation. This signalingmediates vasodilation of the penile, clitoral labial, and vaginalarterial blood vessels and the trabecular meshwork of smooth muscle. Theresulting decrease in vascular resistance promotes an increase inarterial inflow and the filling of the corpora cavernosa in the penisand clitoris. Subsequent to there being an appropriate high rate ofinflow, the cavernosal “filling” results in occlusion of the sub-tunicalveins and full rigidity. The rate of inflow is critical because if thereis not enough volume change, venous occlusion can not take place. Aselective structurally-based increase in penile resistance produces asubstantial impediment to inflow. That is, if penile or clitoralvascular structure, or the vascular structure immediately “up-stream”from the genitalia, is more constrained than the rest of thecirculation, there would be a “mismatching” of perfusion pressure andselective resistance, i.e. genital arterial insufficiency. On the otherhand, it is likely that when hypertension is first established and thereis a generalized up-regulation of structurally-based vascular resistancein all vessels, there would not be any deleterious effect on erectilefunction because of a “matching” between perfusion pressure andresistance. That is, despite the hypertrophy of the penile vasculature,the arterial pressure is proportionally elevated thereby allowing foradequate blood flow to the penis.

Pathological changes in the genital vasculature and alterations infunction control systems have been shown to have a deleterious impact onerectile dysfunction. Local factors such as endothelin and sympatheticnerve mediated release of catecholamines have been shown to be importantplayers in detumescence, but they also are likely to increase trophicresponses in this tissue. The physiology of penile and clitoral erectionand the structural maintenance of the tissue depends upon a balancebetween control systems that involve endothelial cells, vascular smoothmuscle cells, fibroblasts, extracellular matrix, and nerves. Any shiftin the balance of these control systems to either towards trophicresponses such as vascular hypertrophy, focal fibrosis, or generalizedproduction of the extracellular matrix or to the extremes of functionalcontrol systems can result in erectile dysfunction. Further, asstructure and function are so closely related, it is becomingincreasingly important in understanding the mechanisms of erectiledysfunction that we investigate the reciprocal impact of structuralchanges on function and of changes in functional control systems onstructure.

The clitoris is the homologue of the penis, arising from theembryological genital tubercle. As a result, the two organs have similarstructural and arousal response mechanisms. The clitoris consists of acylindrical, erectile organ composed of three parts: the outermost glansor head, the middle corpus or body, and the innermost crura. The body ofthe clitoris consists of paired corpora cavernosa of about 2.5 cm inlength and lacks a corpus spongiosum. During sexual arousal, blood flowto the corpora cavernosa of the clitoris cause their enlargement andtumescence.

The clitoris plays a major role during sexual activity in that itcontributes to local autonomic and somatic changes causing vaginalvasocongestion, engorgement, and subsequent effects, lubricating theintroital canal making the sexual act easier, more comfortable, and morepleasurable.

Vaginal wall engorgement enables a process of plasma transduction tooccur, allowing a flow through the epithelium and onto the vaginalsurface. Plasma transduction results from the rising pressure in thevaginal capillary bed during the sexual arousal state. In addition,there is an increase in vaginal length and lumenal diameter, especiallyin the distal ⅔ of the vaginal canal.

It has been well established that the generation of a penile andclitoral erections and vaginal and labial engorgement are greatlydependent on adequate blood flow to vascular beds which feed theseorgans. Both smooth muscle relaxation of the corpora cavernosa as wellas the vasodilation of genital arterial vessels mediate thephysiological response. One of the major fundamental etiologies oferectile dysfunction is, thus, inadequate genital arterial inflow. Ifthere is an inappropriate structural narrowing in the supportingvasculature that is not associated with an increase in perfusionpressure, the blood flow into the organs at maximum dilation may bereduced and therefore be insufficient for the generation of an erection.There is increasing recognition that erectile dysfunction, althoughassociated with, may appear prior to the onset of clinical signs ofcardiovascular disease and therefore may be an early harbinger ofprogressing changes.

In both the male and female human, the aorta bifurcates on the fourthlumbar vertebra into the common iliac arteries. The common iliacarteries pass laterally, behind the common iliac veins, to the pelvicbrim. At the lower border of the fifth lumbar vertebra, the common iliacarteries divide into internal and external branches. The internal iliacartery supplies blood to all of the organs within the pelvis and sendbranches through the greater sciatic notch to supply the gluteal musclesand perineum. After passing over the pelvic brim, the internal iliacartery divides into anterior and posterior trunks.

The anterior trunk of the internal iliac artery branches into thesuperior vesical artery, the inferior vesical artery, the middle rectalartery, the uterine artery, the obturator artery, the internal pudendalartery, and the inferior gluteal artery. The internal pudendal arterysupplies blood to the perineum. The artery passes out of the pelvisaround the spine of the ischium and back on the inside surface of theischeal tuberosity and inferior ramus to lie in the pudendal canal. Thebranches from the internal pudendal artery are the inferior rectalartery which supplies the anal sphincter, skin and lower rectum; theperineal artery which supplies the scrotum in the male and the labia inthe female; the artery of the bulb which supplies erectile tissue, thedeep dorsal arteries of the penis or deep artery of the clitoris.

It has been demonstrated in several forms of experimental hypertensionthat “slow pressor mechanisms” such as hypertrophic structural changesin the vasculature can almost completely account for the long-termresistance changes associated with the elevated arterial pressure. Basedon Poiseuille's law, it has been shown that vascular resistance in anintact vascular bed is a function of the overall hemodynamic effect ofall lumen radii, the number of blood vessels, the length of the vesselsand the blood viscosity. In hypertension, increased vascular resistanceis most potently conferred by a structurally-based decrease in theradius of the lumen of arterioles and small arteries and alsopotentially by arteriolar rarefaction whereby even a small change in theaverage arteriolar radii throughout a vascular bed has a dramaticinfluence on the resistance to flow. Further, it has been demonstratedthat such structural changes can precede the onset of hypertension andtherefore may be an initiating mechanism.

Vascular beds in which there is chronic diminished blood flow suffer adegree of pathogenic vascular degradative modeling over time in responseto static or circulatory hypoxia. That is, as a normal reaction todiminished blood flow, the lumen in these arteries diminishes indiameter over time, causing decreased blood flow and/or higher pressureduring periods of peak blood flow. Those portions of theilio-hypogastric-pudendal arterial bed which directly feed blood to thesex organs are examples of such less frequently used arterial beds.Because incidents of major blood inflow to the sexual organs are lessfrequent than to most other organs, a gradual hypoxic response is seenover time in the vasculature directly feeding these organs and in theorgans themselves. The body has a self-regulating mechanism to combatthis pathogenic modeling: it is known, for example, that in the humanmale there are a number of spontaneous nocturnal erections which occuras a result of the body's mechanism for combating hypoxia in peniletissue. Nevertheless, the arteries in a normal flaccid penis and theun-enlarged clitoris and labia are constricted. As a result, typicaloxygen concentrations in such tissues are closer to venous rather thanarterial oxygen levels. Periodic vasodilation of the penis and clitorisincreases oxygen levels in these tissues. The higher oxygen levelssupplied to tissue in the penis and clitoris, as well as vasodilationitself, shut down adverse metabolic processes such as TGF-b productionand pathogenic vascular wall modeling which result in long term tissuedamage.

Therefore, it is differential changes in genital vascular resistancethat is likely to be a critical issue in erectile function. That is, ifsuch vascular structural changes take place in the genitalia in theabsence of hypertension or systemic changes in vessel structure therewould not be the increase in arterial pressure required to compensatefor the increased resistance. It may be that this condition could occuras an early indicator of progressing cardiovascular disease. Theappearance of erectile dysfunction preceding the global clinical signsof hypertension may, in fact, suggest an increased susceptibility ofthis vascular bed to pathological changes.

SUMMARY OF THE INVENTION

In its principal embodiment, the present invention provides a method forthe long term management of sexual dysfunction in males and females byadministering a therapeutic agent which remodels neuronal or vascularpathways. In a preferred embodiment, the invention provides a method ofameliorating, inhibiting or reversing pathogenic vascular degradativemodeling in the ilio-hypogastric-pudendal arterial bed and genitaliacomprising administering to a human patient in need of such treatment atherapeutically effective amount of an anti-pressor agent. In oneembodiment, the present invention provides the use of an anti-pressoragent for the manufacture of pharmaceutical compositions forameliorating, inhibiting or reversing pathogenic vascular degradativemodeling in the ilio-hypogastric-pudendal arterial bed and genitalia.

The anti-pressor agent is administered chronically at low doses rangingbetween about one-twentieth to about one-half the dose required to evokevasodilation in a patient exhibiting normal circulation or,alternatively, is administered over a period of time ranging betweenabout five days to about 21 days at higher doses ranging between about1.5 to about 3 times the dose required to evoke vasodilation in apatient exhibiting normal circulation.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

In the Drawing:

FIG. 1 is a representative cumulative α₁-adrenoreceptorconcentration-response curve for administration of several doses ofmethoxamine (MXA) to a spontaneously hypertensive rat. Arrows indicatethe point of drug delivery to the penile vascular bed at theconcentrations labeled in the Figure. Each concentration of MXA wasinfused for a period of ten minutes, at which time a plateau wasreached. The point marked “yield” in the Figure represents the pressureat maximum constriction of the blood vessels in the vascular bed. Thismaximum constriction was achieved by administration of a “cocktail”containing a mixture of vasopressin (20 μg/mL), angiotensin-II (200μg/mL), and methoxamine (64 μg/mL).

FIG. 2 shows the average α₁-adrenoreceptor concentration-response curvesfor administration of methoxamine (MXA) to both the penile vascular bedand hindlimb vascular bed perfusion preparations of the spontaneoushypertensive rat (SHR) and the normotensive Sprague-Dawley rat (SD).FIGS. 2a and 2 b represent, respectively, the curves for administrationto the penile vascular beds of the SHR and SD rat strains. FIGS. 2c and2 d represent, respectively, the curves for administration to thehindlimb vascular beds of the SHR and SD rat strains.

FIG. 3a shows the structurally-based vascular resistance asserted atmaximum dilation for the penile and hindlimb perfusion vascularpreparations for the spontaneously hypertensive rat (SHR) and thenormotensive Sprague-Dawley rat (SD).

FIG. 3b shows the corresponding structurally-based vascular resistanceasserted at maximum constriction for the penile and hindlimb perfusionvascular preparations for the spontaneously hypertensive rat (SHR) andthe normotensive Sprague-Dawley rat (SD).

FIG. 4 is a schematic representation depicting structural differences inblood vessels in the spontaneously hypertensive rat (SHR) and thenormotensive Sprague-Dawley rat (SD) and the expected impact onresistance to blood flow.

DETAILED DESCRIPTION

The present invention contemplates the use of anti-pressor agents toremodel vasculature in the arterial beds supplying blood to the sexorgans, and in the vascularity of the sex organs themselves. There hasbeen some controversy in the literature as to the correct definition ofthe term “vascular remodeling,” as evidenced by the exchange of lettersin the Journal of Hypertension, 15: 333-337 (1997). The controversy inthe nomenclature centers, in part, around the use of the terms“hypotrophic,” “eutrophic,” and “hypertrophic” as modifiers for the term“remodeling” as well as the use of the prefix “re-” in the word“remodeling.”

The “trophic” terms have been objected to because of their suggestionthat some sort of growth change accompanies the observed vascularchanges. The term “remodeling” was initially applied in the literatureto the observation in spontaneously hypertensive rats and inhypertensive humans that the interior lumen radius (r₁) of blood vesselswas greatly diminished while vessel wall mass (w) remained constant. Theresult was an observed increase in the ratio of w/r₁ which correlatedwith blood pressure elevation. The term “remodeling” was applied to theobserved phenomenon, primarily because of the surprising consistency intotal wall mass. It was thought that some sort of remodeling of theinternal cellular structure of the blood vessel had occurred whichpermitted a change in lumen radius without a corresponding change invessel wall mass.

The “re-” prefix has been objected to mainly because of the suggestionthat some sort of “modeling” of the vasculature has already occurred,and subsequent changes (for good or ill) result in a “re-”modeling ofthose changes.

Lacking a general consensus of the term “vascular remodeling” in themedical community, the term “pathogenic vascular degradative modeling”will be applied, throughout this specification and the appended claims,to denote the pathogenic or degradative increase in the ratio w/r₁ ofvasculature, irrespective of the cause. The term “vascular remodeling”as used throughout this specification and the appended claims will meanthe amelioration, inhibition or reversal of pathogenic vasculardegradative modeling; that is the amelioration, inhibition or reversalof the increase in the ratio of vascular w/r₁.

The term “anti-pressor agent” as used herein denotes a therapeutic agentwhich acts either directly or indirectly to lower blood pressure. Theterm anti-pressor agent is chosen, rather than the more specific term“antihypertensive” agent, because the invention contemplates the use ofagents which are effective to increase vascular flow in bothhypertensive and normotensive patients. Anti-pressor agents contemplatedfor use in the method of the present invention include agents which actto bring about a lowering of blood pressure by any of a number ofdifferent physiological mechanisms. Anti-pressor agents includecompounds belonging to a number of therapeutic classes based upon theirmechanism of action, even though the therapeutic outcome is the same.Anti-pressor agents suitable for the method of this invention includecompounds which are direct-acting vasodilators such as NO donors andhydralazine. Other suitable anti-pressor agents are compounds which actto inhibit the enzyme which converts the less potent decapeptidevasoconstrictor, angiotensin-I, to the more potent octapeptidevasoconstrictor, angiotensin II (so-called angiotensin-II convertingenzyme inhibitors or “ACE inhibitors”), as well as agents which blockthe binding of angiotensin-II to the AT₁ receptor (“angiotensin-IIreceptor antagonists”). Anti-pressor agents useful in the method of thepresent invention also include vasodilating agents which act atα₁-adrenergic receptors or β-adrenergic receptors in the smooth muscleof vascular walls (“α₁-adrenergic receptor antagonists” and“β-adrenergic receptor antagonists”), as well as agents which act todecrease intracellular calcium ion concentration in arterial smoothmuscle (“calcium channel blockers”). Suitable anti-pressor agents foruse in the present invention also include activators of the enzymesguanylyl cyclase and adenyl cyclase such as YC-1 and forskolin,respectively. PGE₁ (prostaglandin-E₁), which acts both as ananti-pressor agent and as a sexual response initiator, is also suitablefor use in the invention. Also contemplated as falling within the scopeof the invention for use as anti-pressor agents are phosphodiesteraseinhibiting agents, particularly type-3 and type-5 phosphodiesteraseinhibitors. Antagonists of PDE-5 (phosphodiesterase type 5), the enzymeprimarily responsible for the degradation of cyclic guanosinemonophosphate (cGMP), produce an increase in levels of cGMP, which, byway of “cross-talk,” also decreases the activity of PDE-3, the enzymeprimarily responsible for the degradation of cyclic adenosinemonophosphate (cAMP). Thus, increasing levels of cGMP acts to inhibitthe PDE-3 enzyme, thereby blocking the degradation of cAMP and causingan increase in cAMP levels. Thus, inhibition of either PDE-5 or PDE-3results in an overall increase in concentrations of cAMP and cGMP.

Specific examples of NO donors include glyceryl trinitrate, isosorbide5-mononitrate, isosorbide dinitrate, pentaerythritol tetranitrate,sodium nitroprusside, 3-morpholinosydnonimine, molsidnomine,S-nitroso-N-acetylpenicillamine, S-nitrosoglutathione,N-hydroxyl-L-arginine, S,S-dinitrosodthiol, and NO gas.

ACE inhibitors include benzazapine compounds such as benazepril, andlibenzapril; 6H-pyridazino[1,2-a]diazepine derivatives such ascilazapril; 2,3-dihydro-1H-indene compounds such as delapril; L-prolinederivatives such as alacepril, captopril, ceronapril, enalapril,fosinopril, lisinopril, moveltipril and spirapril; oxoimidazolinederivatives such as imidapril; 1,4-dihydropyridine compounds such aslacidipine; iso-quinoline carboxylic acid derivatives such as moexipriland quinapril; 1H-indole carboxylic acid derivatives such as pentopriland perindopril; hexahydroindole carboxylic acid derivatives such astrandolapril; cyclopenta[b]pyrrole carboxylic acid derivatives such asramipril; and 1,4-thiazepine compounds such as temocapril.

Angiotensin-II receptor antagonists useful as anti-pressor agents in themethod of this invention include eprosartan, irbesartan, losartan, andvalsartan.

α₁-Adrenergic receptor antagonists include substituted phenylderivatives such as midrodrine, phenoxybenzamine, tamsulosin;substituted naphthyl derivatives such as naphazoline; aminoquinazolinederivatives such as alfuzosin, bunazosin, doxazosin, prazosin, terazosinand trimazosin; benzamide compounds such as labetolol; carbazolederivatives such as carvedilol; dimethyluracil derivatives such asurapidil; imidazolidinyl derivatives such as apraclonidine, clonidine;dihydroimidazole derivatives such as phentolamine; indole derivativessuch as indoramin; and 1,2,4-triazolo[4,3-α]pyridine compounds such asdapiprazole.

Calcium channel blockers include benzothiazepine compounds such asdiltiazem; dihydropyridine compounds such as nicardipine, nifedipine,and nimopidine; phenylalkylamine compounds such as verapamil;diarylaminopropylamine ether compounds such as bepridil; andbenimidazole-substituted tetralin compounds such as mibrefadil.

Phosphodiesterase inhibitors include bipyridone compounds such asamrinone; and dihydropyrazolopyrimidine compounds such as sildenafil.Sildenafil functions as a selective type-5 (i.e. c-GMP specific)phosphodiesterase inhibitor, and acts to decrease the metabolism ofc-GMP, the second messenger in nitric oxide mediated erectile response.An oral formulation of this medication has proven to be safe andeffective in improving erectile duration and rigidity. In females,nitric oxide/NOS exists in human vaginal and clitoral tissue.Sildenafil, alone or in combination with other vasoactive agents, iseffective for the long term management of sexual dysfunction for thetreatment of vasculogenic male or female sexual dysfunction.

Pharmaceutical Compositions

Pharmaceutical compositions which are useful in the method of thepresent invention comprise one or more compounds defined aboveformulated together with one or more non-toxic pharmaceuticallyacceptable carriers. The pharmaceutical compositions may be speciallyformulated for oral administration in solid or liquid form, forparenteral injection, or for vaginal or rectal administration. Theformulations may, for example, contain a single therapeutic agentselected from ACE inhibitors, angiotensin-1 (AT₁) receptor antagonists,α₁-adrenoreceptor antagonists, β-adrenergic receptor antagonists,direct-acting vasodilators, NO donors, calcium channel blockers,phosphodiesterase inhibitors, or a combination of two or more agentsselected from the same or different therapeutic categories. Moreover, acombination of one or more therapeutic agents from the groups listedabove may be combined with a diuretic agent of the class well known inthe art.

To enhance delivery to genital vasculature, combined systemic deliverywith topical administration of an erectogenic initiator is alsocontemplated within the scope of this invention. In this manner theanti-pressor drug is delivered to target regions at a markedly enhancedrate. Since prostaglandin-E₁ acts both as an anti-pressor and as adirect sexual response initiator, one or more therapeutic agents fromthe groups listed above can be administered in combination therapy withprostaglandin PGE₁. The co-administered PGE₁ may be administered by anyof the routes discussed below, with topical application being apreferred route.

The pharmaceutical compositions of this invention can be administered toeither systemically or locally to humans and other animals. Systemicroutes include oral, parenteral, intracisternal, intraperitoneal,trans-cutaneous (by injection or patch), buccal, sub-lingualadministration, or by means of an oral or nasal spray. The term“parenteral” administration as used herein refers to modes ofadministration which include intravenous, intramuscular,intraperitoneal, intrasternal, subcutaneous and intraarterial injectionand infusion. Local administration routes include vaginal, rectal,intraurethral, trans-urethral, by intra-cavernosal injection, or topicaladministration.

Pharmaceutical compositions of this invention for parenteral injectioncomprise pharmaceutically acceptable sterile aqueous or nonaqueoussolutions, dispersions, suspensions or emulsions as well as sterilepowders for reconstitution into sterile injectable solutions ordispersions just prior to use. Examples of suitable aqueous andnonaqueous careers, diluents, solvents or vehicles include water,ethanol, polyols (such as glycerol, propylene glycol, polyethyleneglycol, and the like), and suitable mixtures thereof, vegetable oils(such as olive oil), and injectable organic esters such as ethyl oleate.Proper fluidity can be maintained, for example, by the use of coatingmaterials such as lecithin, by the maintenance of the required particlesize in the case of dispersions, and by the use of surfactants.

These compositions may also contain adjuvants such as preservatives,wetting agents, emulsifying agents, and dispersing agents. Prevention ofthe action of microorganisms may be ensured by the inclusion of variousand bacterial and antifungal agents, for example, paraben,chlorobutanol, phenol sorbic acid, and the like. It may also bedesirable to include isotonic agents such as sugars, sodium chloride,and the like. Prolonged absorption of the injectable pharmaceutical formmay be brought about by the inclusion of agents which delay absorptionsuch as aluminum monostearate and gelatin.

In some cases, in order to prolong the effect of the drug it isdesirable to slow the release or absorption of the drug followingsubcutaneous or intramuscular rejection. This may be accomplished by theuse of a liquid suspension of crystalline or amorphous material with lowwater solubility. The rate of absorption of the drug then depends uponits rate of dissolution which, in turn, may depend upon crystal size andcrystalline form. Alternatively, delayed absorption of a parenterallyadministered drug form is accomplished by dissolving or suspending thedrug in an oil vehicle.

Injectable depot forms are made by forming microencapsule matrices ofthe drug in biodegradable polymers such as polylactide-polyglycolide.Depending upon the ratio of drug to polymer and the nature of theparticular polymer employed, the rate of drug release can be controlled.Examples of other biodegradable polymers include poly(othoesters) andpoly(anhydrides). Depot injectable formulations are also prepared byentrapping the drug in liposomes or microemulsions which are compatiblewith body tissues.

The injectable formulations can be sterilized, for example, byfiltration through a bacterial-retaining filter, or by incorporatingsterilizing agents in the form of sterile solid compositions which canbe dissolved or dispersed in sterile water or other sterile injectablemedium just prior to use.

Solid dosage forms for oral administration include capsules, tablets,pills, powders, and granules. In such solid dosage forms the activecompound is mixed with at least one inert, pharmaceutically acceptableexcipient or carrier such as sodium citrate or dicalcium phosphateand/or a) fillers or extenders such as starches, lactose, sucrose,glucose, mannitol, and silicic acid, b) binders such as, for example,carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone,sucrose, and acacia, c) humectants such as glycerol, d) disintegratingagents such as agar-agar, calcium carbonate, potato or tapioca starch,alginic acid, certain silicates, and sodium carbonate, e) solutionretarding agents such as paraffin, f) absorption accelerators such asquaternary ammonium compounds, g) wetting agents such as, for example,cetyl alcohol and glycerol monostearate, h) absorbents such as kaolinand bentonite clay, and 1) lubricants such as talc, calcium stearate,magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate,and mixtures thereof. In the case, of capsules, tablets and pills, thedosage form may also comprise buffering agents. Solid compositions of asimilar type may also be employed as fillers in soft and hard-filledgelatin capsules using such excipients as lactose or milk sugar as wellas high molecular weight polyethylene glycols and the like.

The solid dosage forms of tablets, dragees, capsules, pills, andgranules can be prepared with coatings and shells such as entericcoatings and other coatings well known in the pharmaceutical formulatingart. They may optionally contain opacifying agents and can also be of acomposition that they release the active ingredient(s) only, orpreferentially, in a certain part of the intestinal tract, optionally,in a delayed manner. Examples of embedding compositions which can beused include polymeric substances and waxes. The active compounds canalso be in micro-encapsulated form, if appropriate, with one or more ofthe above-mentioned excipients.

Liquid dosage forms for oral administration include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups and elixirs. Inaddition to the active compounds, the liquid dosage forms may containinert diluents commonly used in the art such as, for example, water orother solvents, solubilizing agents and emulsifiers such as ethylalcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzylalcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol,dimethyl formamide, oils (in particular, cottonseed, ground nut corn,germ olive, castor, and sesame oils), glycerol, tetrahydrofurfurylalcohol, polyethylene glycols and fatty acid esters of sorbitan, andmixtures thereof. Besides inert diluents, the oral compositions can alsoinclude adjuvants such as wetting agents, emulsifying and suspendingagents, sweetening, flavoring, and perfuming agents.

Suspensions, in addition to the active compounds, may contain suspendingagents as, for example, ethoxylated isostearyl alcohols, polyoxyethylenesorbitol and sorbitan esters, microcrystalline cellulose, aluminummetahydroxide, bentonite, agar-agar, and tragacanth, and mixturesthereof.

Compositions for rectal administration are preferably suppositorieswhich can be prepared by mixing the compounds of this invention withsuitable non-irritating excipients or carriers such as cocoa butter,polyethylene glycol or a suppository wax which are solid at roomtemperature but liquid at body temperature and therefore melt in therectum and release the active compound,

Compounds of the present invention can also be administered in the formof liposomes. As is known in the art, liposomes are generally derivedfrom phospholipids or other lipid substances. Liposomes are formed bymono- or multi-lamellar hydrated liquid crystals that are dispersed inan aqueous medium. Any non-toxic, physiologically acceptable andmetabolizable lipid capable of forming liposomes can be used. Thepresent compositions in liposome form can contain, in addition to acompound of the present invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andthe phosphatidyl cholines (lecithins), both natural and synthetic.Methods for the formation of liposomes are known in the art. See, forexample, Prescott, Ed., Methods in Cell Biology, Volume XIV AcademicPress, New York, N.Y. (1976), p. 33 et seq.

Actual dosage levels of active ingredients in the pharmaceuticalcompositions of this invention may be varied so as to obtain an amountof the active compound(s) that is effective to achieve the desiredtherapeutic response for a particular patient, compositions, and mode ofadministration. The selected dosage level will depend upon the activityof the particular compound, the route of administration, the severity ofthe condition being treated, and the condition and prior medical historyof the patient being treated. However, it is well known within themedical art to determine the proper dose for a particular patient by the“dose titration” method. In this method, the patient is started with adose of the drug compound at a level lower than that required to achievethe desired therapeutic effect. The dose is then gradually increaseduntil the desired effect is achieved. Starting dosage levels for analready commercially available therapeutic agent of the classesdiscussed above can be derived from the information already available onthe dosages employed for the use of the compound as an antihypertensiveagent. In a chronic, or long-term dosing regimen to remodel thevasculature in the genitalia and in vascular beds feeding the genitalia,lower doses ranging between about {fraction (1/20)} to about ½ the dosesnormally given to combat hypertension are used. In short term, acute, or“burst-mode” therapy, the compounds are administered in doses rangingbetween 1 to 3 times the amounts generally prescribed for hypertension.In these situations, however, appropriate precautions should be taken bythe attending physician to closely monitor untoward side-effectspeculiar to each particular therapeutic agent.

For the preferred therapeutic agents in the method of the presentinvention, namely ACE inhibitors, generally dosage levels of about 1 mgto about 300 mg, more preferably of about 5 mg to about 150 mg of activecompound per kilogram of body weight per day are administered orally toa patient, with the dose levels appropriately adjusted if the route ofadministration is other than oral. If desired, the effective daily dosemay be divided into multiple doses for purposes of administration, e.g.two to four separate doses per day.

Biological Data

A. Demonstration that the Sex Organs are Not Protected from PathologicalVascular Degradative Modeling

1 Methodology

Male spontaneously hypertensive (SH) rats weighing between 246-313 g,and normotensive Sprague-Dawley (SD) rats weighing between 246-440 gwere obtained from Charles River Laboratories (Montreal, Quebec,Canada). The animals were maintained in individual cages with a 12 hourlight/12 hour dark cycle, and a room temperature of 22-24° C. They wereprovided with standard rodent chow and tap water ad libitum and wereacclimated to the room for at least two days before the experiments. Allprocedures were carried out in accordance with the guidelines set out bythe Canadian Council on Animal Care.

2. Penile Vascular Resistance Properties

Penile perfusion preparations were made using the procedure establishedby Banting, J. D., et al., “Isolation and Perfusion of the PudendalVasculature in Male Rats. J Urol., 2: 587-590 (1995). A heated chamberserved to maintain the ambient temperature and the entire preparation at37-38° C. The perfusate was held in a reservoir and passed through aheating and a bubble trapping/mixing chamber connected to a singleperistaltic pump (Minipuls 2 Pump, Gilson, Inc., 3000 W. BeltlineHighway, Middleton, Wis. USA 53562). An injection port was locateddistal to the pump for the introduction of pharmacological agents tominimize dead volume. Drugs were administered via a Harvard Apparatus,Inc. infusion pump (Harvard Apparatus, Inc., 84 October Hill Road,Holliston, Mass. 01746). The perfusate was a Tyrode-dextran solutionconsisting of a mixture of 20 mg of KCI, 32.3mg of CaCl₂.H₂O, 5.1 mg ofMgCl₂.6H₂O, 6.2 mg of NaH2PO₄.2H₂O, 155 mg of NaHCO₃, 100 mg of glucose,and 800 mg of NaCl in each 100 mL of fluid. The solution was maintainedat pH 7.4, and a temperature of 37-39° C., and oxygenated with 95% O₂and 5% CO₂. The rats were anaesthetized (sodium pentobarbital 60 mg/kgbody weight i.p.) and heparinized (1000 IU/kg, i.v.). The bilateralisolation of penile vasculature was achieved by ligating all of thebranching arteries except for the pudendal; then the abdominal aorta wascannulated proximal to the iliac bifurcation with a single lumencatheter. The catheter was connected to the perfusion apparatus via apressure transducer for arterial pressure recording. After sectioningthe vena cava and spinal cord to remove venous resistance and toeliminate neural influences, a flow of perfusate (1 mL/min per kg bodyweight) through the abdominal cannula was initiated. The perfusionpressure was continuously recorded on a data acquisition system (MacLab,AD Instruments, Houston, Tex.). The perfusate was infused for twentyminutes to flush the penile vasculature of blood and obtain a stablepressure before the beginning of any experiment. Following this, sodiumnitroprusside (20 μg/mL) was infused to induce maximum vasodilation. Theflow rate-perfusion/pressure relationship was determined by measuringthe pressure at minimum vascular resistance at flow rates of 0.5, 1.0,2.0, 4.0 mL/min per kg of body weight. A cumulative α₁-adrenoreceptorconcentration-response curve to methoxamine (2.5, 5, 10, 25, 50 μg/mLwas then generated. Each concentration of methoxamine was infused for aduration of 10 minutes, at which time a plateau was reached.Subsequently, a continuous injection of a cocktail containing asupramaximal concentration of vasoconstrictors (vasopressin, 20.5 μg/mL,angiotensin-II, 200 ng/mL; methoxamine, 64 μg/mL; Sigma, St. Louis, Mo.,63178) was given to ensure that maximum constrictor response that wasnot dependent upon the activation of a single receptor type wasachieved. A second injection of the constrictor cocktail wasadministered to ensure the tissue “yield” was maximum constriction. This“yield” induced by the multi-vasoconstrictor cocktail has beendemonstrated to correlate directly with the bulk of medial vascularsmooth muscle cells in the resistance vasculature. A typical perfusionpressure tracing from this protocol can be seen in FIG. 1. At the end ofthe concentration-response relationship, the aorta was cut distal to thecatheter, and a baseline flow-pressure curve was recorded again. Thiswas done to ensure that pressure fell to zero and to account for anyfalse pressure readings that may have resulted due to movement of thecatheter during the experiment.

3. Hindlimb Vascular Resistance Properties

The hindlimb perfusion preparation was adopted from a techniqueoriginally designed by Folkow et al., Acta Physiol Scand., 80: 93-106(1973), as modified by Adams et al., Hypertension, 14: 191-202 (1989).The perfusion experiment was performed as described above. Drugs wereadministered into the mixing chamber via a Harvard Apparatus infusionpump. The rats were anaesthetized (Inactin, 100 mg/kg of body weight,i.p.) and heparinized (1000 IU/kg of body weight, i.v.). Following amidline abdominal incision, the abdominal aorta was cannulated proximalto the iliac bifurcation with a double lumen catheter (Storz, St Louis,Mo., USA), and the catheter was extended down the right common iliacartery. One lumen of the catheter was connected to the perfusionapparatus, while the other was connected to a pressure transducer forarterial pressure recording. The rat was perfused at a constant flowrate (2 mL/min per 100 g of body weight) and the experiments werecarried out as described above. The flow rate/perfusion pressurerelationship was recorded at flow rates of 0.5, 1.0, 2.0, 4.0 mL/min per100 g of body weight. A cumulative α₁-adrenoreceptorconcentration-response curve to methoxamine (0.5, 1, 2, 4, 8, 16, 32, 64μg/mL) was then generated. Each concentration of methoxamine was infusedfor a duration of 5 minutes, at which time a plateau was reached.Subsequently, a bolus injection of a cocktail containing a supramaximalconcentration of vasoconstrictors was given as above. At the end of theconcentration-response relationship, the iliac artery was cut distal tothe catheter, and the flow pressure curve was monitored again.

Flow rates for the hindlimb perfusion experiments were determined basedon expected flow rates of exercising skeletal muscle at maximumdilation. The flow rate used resulted in a perfusion pressure at maximumdilation between 20-25 mm Hg which is well within the expected range.After checking several flow rates in the penile perfusion, a rate wasobtained that resulted in a similar perfusion pressure at maximumdilation. The flow rates chosen also allow for the assessment at maximumconstriction. This allowed for comparison between strains.

4. Analysis of Data

All values in the figures and tables were expressed as mean ± standarddeviation. Results comparing penile and hindlimb vasculature wereanalyzed using the Student's t-test. Differences were considered assignificant at p<0.05.

5. Results

There was no significant difference in the body weight of thespontaneously hypertensive rats in the penile assessment group (267±29g, n=5) and in the hindlimb assessment group (270±5.7 g, n=3). Theaverage body weight of the normotensive Sprague-Dawley rats in thehindlimb assessment group (375±41 g, n=8) was significantly higher thanthat of the of the normotensive Sprague-Dawley rats in the penileassessment group (284±32 g, n=5). However, this was not consideredrelevant because in normotensive adult rats there has been shown to bevery little correlation between body weight and blood pressure (Adams,M. A., et al., Hypertension, 14: 191-202 (1989).

This hemodynamic analysis had similar effects in most parameters betweenthe penile and hindlimb vascular beds within each rat strain. Theflow-pressure curve assessed at maximal dilation was similar in both thepenile and the hindlimb vasculatures of spontaneously hypertensive andnormotensive rats as shown in Table 1. These curves were monitored toensure a linear increase in perfusion pressure with an increase in flowrate. The increase in the flow rate exerted a radial pressure againstthe vessel wall and resulted in increased pressure. The spontaneouslyhypertensive rats trended towards a higher baseline pressure than thenormotensive rats. This was observed in both penile and hindlimbvascular beds. These data suggest that spontaneously hypertensive ratsmay have a smaller lumen thus causing them to operate at a higherpressure than normotensive Sprague-Dawley rats even when there is noconstrictor tone on the vessel.

TABLE 1 Maximum Constriction With Methox- Slope amine Slope Group FlowPressure (mm Hg) Log EC₅₀ Methoxamine SHR, 7.15 ± 2.0 172 ± 32 0.95 ±0.19  1.64 ± 0.21 penile bed SHR,  6.68 ± 0.38  253 ± 25* 0.79 ± 0.15 5.19 ± 3.0* hindlimb bed SD, 7.34 ± 2.3 171 ± 36 0.63 ± 0.24  2.03 ±0.68 penile bed SD, 6.99 ± 3.4 191 ± 55 0.78 ± 0.12  3.0 ± 0.99 hindlimbbed * Statistically significant.

Table I shows there was a statistically significant difference inmaximum constriction with a supramaximal dose of methoxamine (50 μg/mLfor penile and 64 μg/mL for hindlimb vasculature) between spontaneouslyhypertensive rat hindlimb vasculature (253±25 mmHg) and spontaneouslyhypertensive rat penile vasculature (172±32 mmHg). This difference wasnot observed in normotensive Sprague-Dawley rats. The discrepancy isnovel and requires further assessment. It is expected that higherresponses would be seen in the spontaneously hypertensive rats in botharterial beds, however only the hindlimb vasculature showed asignificant difference between spontaneously hypertensive andnormotensive rats. Average concentration response curves for methoxamineof the two strains in both beds are shown in FIGS. 2a-2 d.

The EC₅₀ of the concentration response curve shown in Table 1 gives theconcentration of drug at which there is a 50% response toα₁-adrenoreceptor stimulation. This value would be an indication of thesensitivity of the tissue to this receptor activation. The logs EC₅₀ ofthe methoxamine concentration-response curves were not different forpenile and hindlinb vasculature in both the spontaneously hypertensiveand normotensive rats thus indicating similar sensitivity to thisreceptor stimulation.

The steepest slope of this curve is given in Table 1. In normotensiverats, there was no statistically significant difference in slope betweenpenile vasculature (2.03±0.68) and hindlimb vasculature (3.0±0.99). Theparameters showed a statistically significant difference betweenspontaneously hypertensive rat penile (1.64±0.21) and spontaneouslyhypertensive rat hindlimb (5.19±3.0). This was expected since themaximal constriction with methoxamine was lower in penile vasculaturewhile the EC₅₀, remained the same.

FIG. 3 depicts the structurally-based vascular resistance propertiesassessed at both maximum dilation and maximum constriction. There was nosignificant difference in perfusion pressures at maximum dilation withinthe rat strains. Between the two strains of rats, the penile vasculaturetrended towards higher pressures in the hypertensive rat as compared tothe normotensive Sprague-Dawley rats, however it did not reach a levelof significance as in the hindlimb. Spontaneously hypertensive ratsreached a point of maximal constriction with a cocktail at a perfusionpressure that was 20% higher than normotensive rats in each vascularbed. There was no statistically significant difference between the twobeds within strain, suggesting that the penile and hindlimb vasculatureundergo similar structural changes in genetically hypertensive rats.This point demonstrates the increased medial thickening that occurs inthe hypertensive rats that allows for the maintenance of higher arterialoperating pressures.

6. Discussion

The major findings of the data presented above demonstrate that thepenile vasculature is not protected from the structural changes thattake place in the other vascular beds of spontaneously hypertensive ratsrelative to normotensive strains. Increased medial thickening andnarrowing of the vascular lumen have been found in blood vessels of awide range of vascular beds of spontaneously hypertensive rats.Therefore, the overall results of the present series of experiments haveshown that the genetic disposition appears to dominate the structureregardless of the vascular bed.

In the present study a hemodynamic methodology was used to compare andcontrast structurally-based vascular resistance in two vascular beds.The hindlimb bed was chosen for comparison since the vascular resistanceproperties are well established and anatomically the feeder vessels ofthe two beds are common.

These results demonstrate that the resistance properties at maximumdilation were similar in the two beds within strains. A general findingof studies comparing vascular resistance at minimum tone is that ahigher perfusion pressure is normally obtained in SHR compared tonormotensive rats. Thus, findings of elevated resistance properties atmaximum dilation are consistent with there being an overall narrowing ofthe vascular lumen. Resistance properties were further assessed bydetermining the slope of the flow-pressure curve at maximum dilation.This relationship was used to determine whether there were anydifferences in the passive vascular wall elements such as theextracellular matrix components, i.e. if distensibility was alteredthere would be a differential effect on the flow-pressure curves.Further, a thicker medial wall could also result in a stiffer vesselwhich would exhibit less compliance with increasing flow. The lack ofdifference in all of these values suggests that there has been nodifferential change in the components of the vessel wall within thepenile vasculature.

Assessment of the active components of the vessel walls was determinedby inducing a state of maximal vasoconstrictor tone using a cocktail ofvasoconstrictor agonists. The supramaximal, multiple agonist stimulusproduces a maximum constrictor response which is independent ofindividual receptor population changes thereby reflecting only theoverall contractile bulk of the medial smooth muscle cells.

The findings that sensitivity (EC₅₀) and reactivity (slope) toα₁-adrenoreceptor stimulation were not different between vascular bedsor strains likely indicates that there is a similar stimulus-responsecoupling of the noradrenergic innervation in all of these vessels; i.e.there is a consensus of normal vascular biology. In the schematicdiagram of FIG. 4, the concept of structural changes dominating functionis depicted. Thus, the curves show that, at any given level ofvasoconstrictor tone, the hypertensive circulation will always haveincreased vascular resistance compared to normotensive circulation.Another way of looking at this concept would be that at the same levelof constrictor tone, the normotensive circulation would be able toachieve the same inflow at a proportionately lower perfusion pressurethan the hypertensive circulation.

Taken together, the findings indicate that the penile vasculature has anincreased average medial mass coupled with decreased average lumen. Thegeneration of an erection is based on the flow when vessels are in adilated state. Although there was a significant difference in theperfusion pressure at maximum dilation in the hindlimb vasculature ofspontaneously hypertensive rats (SHR) when compared to the normotensiveSprague-Dawley (SD) rats, this was not detected in the penile vascularbed. There was however a trend toward significance which may be seen infuture studies when animals are used that are genetically closer to thespontaneously hypertensive rat, such as the Wistar-Kyoto rat (Taconic,273 Hover Avenue, Germantown, N.Y. 12526) which is a more appropriatenormotensive control. The penile vasculature is more complex than thatof the hindlimb and therefore it may be that differences at maximumdilation are more difficult to detect. It is also unknown whether thesize of the penis differs between the strains examined in this study.The length of the vessels changes baseline resistance more than themaximum constriction response because the maximum dilation isflow-dependent, as there is no constrictor tone on the vessel. Incontrast, maximum constriction responses are based on the bulk musculartissue. Therefore although the point of maximum dilation is expected tobe higher in the penile vasculature of SHR as compared to a normotensivecontrol it may not be detectable using the Sprague-Dawley rats as acomparison based on the suspected differences between the strains.

B. Therapeutically-induced Vascular Remodeling in Penile Vasculature

1. Methodology

Adult spontaneously hypertensive rats (SHR) were treated for 1 or twoweeks with either enalapril (30 mg/kg of body weight per day) orhydralazine (45 mg/kg of body weight per day). Following this treatment,structurally-based resistance to blood flow in the perfused penilevascular bed and hindlimb vascular bed models were measured using themethods detailed above. Cumulative α₁-adrenoreceptorconcentration-response curves in response to methoxamine were measuredas described above, and the “yield” point determined, following theachievement of maximal vasoconstriction using the vasopressin,angiotensin-II, methoxamine cocktail described above. The animal heartswere excised and weighed. The data are presented in Table 2 below.

TABLE 2 Left Maximum Ventricle Constriction Weight (g)/ Slope WithCocktail Body Flow “Yield” Weight Group Pressure mm Hg) Log EC₅₀ (kg)Ratio SHR-E₂ ¹ 6.45 ± 1.31 335 ± 23 8.73 ± 0.26 2.13 ± 0.08 (n = 7)SHR-E₁ ¹ 6.10 ± 1.5  358 ± 20 7.33 ± 1.39 2.17 ± 0.05 (n = 5) SHR-H²6.63 ± 0.86 353 ± 11 13.56 ± 5    2.37 ± 0.12 (n = 7) Control 7.13 ±0.63 381 ± 21 11.95 ± 5.51  2.46 ± 0.08 (n = 9) ¹Enalapril-treatedanimals. ²Hydralazine-treated animals

The data appearing in Table 2 show that enalapril treatmentprogressively regressed (remodeled) cardiac and pudendal vascularstructure over the 2-week period of treatment. The “yield” valuedecreased on average by 12.1%±6.0%, while left ventricular massdecreased by 13.6%±3.2%. Hydralazine treatment was somewhat lesseffective, decreasing the “yield” point by 7.3%±2.9%, and had nosignificant effect on left ventricular weight (decreased of 3.7%±5.0%).

While there have been shown and described what are believed at presentto be the preferred embodiments of the present invention, it will beobvious to those of ordinary skill in the art that various modificationscan be made in the preferred embodiments without departing from thescope of the invention as it is defined by the appended claims.

We claim:
 1. A method of ameliorating, inhibiting or reversingpathogenic vascular degradative modeling in theilio-hypogastric-pudendal arterial bed and genitalia, comprisingadministering to a human patient in need of such treatment atherapeutically effective amount of an anti-pressor agent at a dose thatis from about one-twentieth to about one-half the dose required to evokevasodilation in a patient exhibiting normal circulation, wherein saidanti-pressor agent comprises one or more compounds selected fromprostaglandin-E₁, β-adrenergic receptor antagonists, amrinone, andsildenafil.
 2. The method of claim 1 wherein said anti-pressor agent isprostaglandin-E₁.
 3. The method of claim 1 wherein said anti-pressoragent is a β-adrenergic receptor antagonist.
 4. The method of claim 1wherein said anti-pressor agent is amrinone.
 5. The method of claim 1wherein said anti-pressor agent is sildenafil.
 6. The method of claim 1wherein said anti-pressor agent is co-administered with a diureticcompound.
 7. The method of claim 1 wherein said anti-pressor agent isadministered to a normotensive patient.
 8. The method of claim 1 whereinsaid anti-pressor agent is administered on a chronic basis at a doseranging between one-twentieth to one-half the dose normally given to ahypertensive patient.
 9. The method of claim 1 wherein said anti-pressoragent is administered for a period ranging between about three days toabout twenty-one days.
 10. The method of claim 8 wherein saidanti-pressor agent is administered to a normotensive patient.
 11. Themethod of claim 9 wherein said anti-pressor agent is administered to anormotensive patient.
 12. A method of ameliorating, inhibiting orreversing pathogenic vascular degradative modeling in theilio-hypogastric-pudendal arterial bed and genitalia. comprisingadministering to a human patient in need of such treatment atherapeutically effective amount of at least one ACE inhibitor at a dosethat is from about one-twentieth to about one-half the dose required toevoke vasodilation in a patient exhibiting normal circulation.
 13. Themethod of claim 12 wherein said ACE inhibitor is alacepril.
 14. Themethod of claim 12 wherein said ACE inhibitor is benazepril.
 15. Themethod of claim 12 wherein said ACE inhibitor is captopril.
 16. Themethod of claim 12 wherein said ACE inhibitor is ceronapril.
 17. Themethod of claim 12 wherein said ACE inhibitor is cilazapril.
 18. Themethod of claim 12 wherein said ACE inhibitor is delapril.
 19. Themethod of claim 12 wherein said ACE inhibitor is enalapril.
 20. Themethod of claim 12 wherein said ACE inhibitor is fosinopril.
 21. Themethod of claim 12 wherein said ACE inhibitor is imidapril.
 22. Themethod of claim 12 wherein said ACE inhibitor is lacidipine.
 23. Themethod of claim 12 wherein said ACE inhibitor is libenzapril.
 24. Themethod of claim 12 wherein said ACE inhibitor is lisinopril.
 25. Themethod of claim 12 wherein said ACE inhibitor is moexipril.
 26. Themethod of claim 12 wherein said ACE inhibitor is moveltipril.
 27. Themethod of claim 12 wherein said ACE inhibitor is pentopril.
 28. Themethod of claim 12 wherein said ACE inhibitor is perindopril.
 29. Themethod of claim 12 wherein said ACE inhibitor is quinapril.
 30. Themethod of claim 12 wherein said ACE inhibitor is ramipril.
 31. Themethod of claim 12 wherein said ACE inhibitor is spirapril.
 32. Themethod of claim 12 wherein said ACE inhibitor is temocapril.
 33. Themethod of claim 12 wherein said ACE inhibitor is trandolapril.
 34. Themethod of claim 12 wherein said ACE inhibitor is co-administered with adiuretic compound.
 35. The method of claim 12 wherein said ACE inhibitoris administered to a normotensive patient.
 36. The method of claim 12wherein said ACE inhibitor is administered on a chronic basis at a doseranging between one-twentieth to one-half the dose normally given to ahypertensive patient.
 37. The method of claim 12 wherein said ACEinhibitor is administered for a period ranging between about three daysto about twenty-one days.
 38. The method of claim 36 wherein said ACEinhibitor is administered to a normotensive patient.
 39. The method ofclaim 37 wherein said ACE inhibitor is administered to a normotensivepatient.
 40. A method of remodeling the vascular bed which suppliesblood to the genitalia, comprising administering to a patient in needthereof a therapeutically effective amount of an anti-pressor agent at adose that is from about one-twentieth to about one-half the doserequired to evoke vasodilation in a patient exhibiting normalcirculation, wherein said anti-pressor agent comprises one or morecompounds selected from prostaglandin-E₁, β-adrenergic receptorantagonists, amrinone, and sildenafil.
 41. The method of claim 40wherein said anti-pressor agent is prostaglandin-E₁.
 42. The method ofclaim 40 wherein said anti-pressor agent is a β-adrenergic receptorantagonist.
 43. The method of claim 40 wherein said anti-pressor agentis a amrinone.
 44. The method of claim 40 wherein said anti-pressoragent is sildenafil.
 45. The method of claim 40 wherein saidanti-pressor agent is co-administered with a diuretic compound.
 46. Themethod of claim 40 wherein said anti-pressor agent is administered to anormotensive patient.
 47. The method of claim 40 wherein saidanti-pressor agent is administered on a chronic basis at a dose rangingbetween one-twentieth to one-half the dose normally given to ahypertensive patient.
 48. The method of claim 40 wherein saidanti-pressor agent is administered for a period ranging between aboutthree days to about twenty-one days.
 49. The method of claim 47 whereinsaid anti-pressor agent is administered to a normotensive patient. 50.The method of claim 48 wherein said anti-pressor agent is administeredto a normotensive patient.
 51. A method of remodeling the vascular bedwhich supplies blood to the genitalia, comprising administering to apatient in need thereof a therapeutically effective amount of at leastone ACE inhibitor at a dose that is from about one-twentieth to aboutone-half the dose required to evoke vasodilation in a patient exhibitingnormal circulation.
 52. The method of claim 51, wherein said ACEinhibitor is enalapril.
 53. The method of claim 51 wherein said ACEinhibitor is co-administered with a diuretic compound.
 54. The method ofclaim 51 wherein said ACE inhibitor is administered to a normotensivepatient.
 55. The method of claim 51 wherein said ACE inhibitor isadministered on a chronic basis at a dose ranging between one-twentiethto one-half the dose normally given to a hypertensive patient.
 56. Themethod of claim 51 wherein said ACE inhibitor is administered for aperiod ranging about three days to about twenty-one days.
 57. The methodof claim 55 wherein said ACE inhibitor is administered to a normotensivepatient.
 58. The method of claim 56 wherein said ACE inhibitor isadministered to a normotensive patient.